To become insulin independent, patients with type 1 diabetes mellitus require transplantation of at least two donor pancreata because of massive β–cell loss in the early post‐transplantation period. Many studies describing the introduction of new immunosuppressive protocols have shown that this loss is due to not only immunological events but also nonimmunological factors. To test to what extent hypoxia may contribute to early graft loss, we analyzed the occurrence of apoptotic events and the expression of hypoxia‐inducible factor 1 (HIF‐1), a heterodimeric transcription factor consisting of an oxygen‐dependent α subunit and a constitutive β subunit. Histological analysis of human and rat islets revealed nuclear pyknosis as early as 6 h after hypoxic exposure (1% O₂). Moreover, immunoreactivity to activated caspase‐3 was observed in the core region of isolated human islets. Of note, both of these markers of apoptosis topographically overlap with HIF‐1α immunoreactivity. HIF‐1α mRNA was detected in islets from human and rat as well as in several murine β–cell lines. When exposed to hypoxia, mouse insulinoma cells (MIN6) had an increased HIF‐1α protein level, whereas its mRNA level did not alter. In conclusion, our data provide convincing evidence that reduced oxygenation is an important cause of β–cell loss and suggest that HIF‐1α protein level is an indicator for hypoxic regions undergoing apoptotic cell death. These observations suggest that gene expression under the control of HIF‐1 represents a potential therapeutic tool for improving engraftment of transplanted islets.